Advertisement

The utility of the “Glowing Head” mouse for breast cancer metastasis research

  • Mohammad A. Alzubi
  • David C. Boyd
  • J. Chuck HarrellEmail author
Technical Note
  • 66 Downloads

Abstract

The expression of cellular reporters to label cancer cells, such as green fluorescent protein (GFP) and luciferase, can stimulate immune responses and effect tumor growth. Recently, a mouse model that expresses GFP and luciferase in the anterior pituitary gland was generated to tolerize mice to these proteins; the “Glowing Head” mouse. Mice were obtained from a commercial vendor, bred, and then used for tumor growth and metastasis studies. The transgene expression of luciferase was assessed within tumor-naïve mice as well as mice with mammary tumors or metastases. Tumor-free mice with white fur, compared to black fur, allowed for stronger luciferase transgene expression to be observed in the pituitary, sternum, and femur. Growth of four different luciferase-expressing mouse cancer cell lines readily occurred in the mammary gland. Though sternum expression of the luciferase transgene occurred in cancer-free mice, growth or death of luciferase positive cancer cells in the lung could be observed. Liver metastases seeded by portal vein injections of luciferase positive cancer cell lines were completely distinct from luciferase transgene expression. Though lung and brain metastasis studies have limitations, the Glowing Head mouse can be useful to inhibit immune system rejection of luciferase or GFP expressing cancer cells. This mouse model is most beneficial for studies of mammary tumors and liver metastases.

Keywords

Luciferase IVIS imaging Glowing head mouse PyMT Metastasis 

Notes

Acknowledgements

IVIS imaging was performed with instrumentation by the Cancer Mouse Models Shared Resource Core supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059. This work was supported by funds to JCH by the VCU Massey Cancer Center.

Author contributions

Designed experiments; MAA, DCB, JCH, performed cell experiments; MAA, DCB, performed animal experiments; MAA, wrote the manuscript; DCB, JCH, supervised the study; JCH, all authors reviewed and edited the manuscript.

Compliance with ethical standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Ericsson AC, Crim MJ, Franklin CL (2013) A brief history of animal modeling. Mo Med 110(3):201–205PubMedPubMedCentralGoogle Scholar
  2. 2.
    Hart IR, Fidler IJ (1980) Role of organ selectivity in the determination of metastatic patterns of B16 melanoma. Cancer Res 40(7):2281–2287PubMedGoogle Scholar
  3. 3.
    Fidler IJ (1970) Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with 125 I-5-iodo-2'-deoxyuridine. J Natl Cancer Inst 45(4):773–782PubMedGoogle Scholar
  4. 4.
    Brunner N, Thompson EW, Spang-Thomsen M, Rygaard J, Dano K, Zwiebel JA (1992) lacZ transduced human breast cancer xenografts as an in vivo model for the study of invasion and metastasis. Eur J Cancer 28A(12):1989–1995CrossRefGoogle Scholar
  5. 5.
    Chishima T, Yang M, Miyagi Y, Li L, Tan Y, Baranov E, Shimada H, Moossa AR, Penman S, Hoffman RM (1997) Governing step of metastasis visualized in vitro. Proc Natl Acad Sci USA 94(21):11573–11576CrossRefGoogle Scholar
  6. 6.
    Hoffman RM (2005) The multiple uses of fluorescent proteins to visualize cancer in vivo. Nat Rev Cancer 5(10):796–806CrossRefGoogle Scholar
  7. 7.
    Yang M, Baranov E, Jiang P, Sun FX, Li XM, Li L, Hasegawa S, Bouvet M, Al-Tuwaijri M, Chishima T, Shimada H, Moossa AR, Penman S, Hoffman RM (2000) Whole-body optical imaging of green fluorescent protein-expressing tumors and metastases. Proc Natl Acad Sci USA 97(3):1206–1211CrossRefGoogle Scholar
  8. 8.
    Bourett TM, Sweigard JA, Czymmek KJ, Carroll A, Howard RJ (2002) Reef coral fluorescent proteins for visualizing fungal pathogens. Fungal Genet Biol 37(3):211–220CrossRefGoogle Scholar
  9. 9.
    Harrell JC, Dye WW, Allred DC, Jedlicka P, Spoelstra NS, Sartorius CA, Horwitz KB (2006) Estrogen receptor positive breast cancer metastasis: altered hormonal sensitivity and tumor aggressiveness in lymphatic vessels and lymph nodes. Cancer Res 66(18):9308–9315CrossRefGoogle Scholar
  10. 10.
    Harrell JC, Dye WW, Harvell DM, Pinto M, Jedlicka P, Sartorius CA, Horwitz KB (2007) Estrogen insensitivity in a model of estrogen receptor positive breast cancer lymph node metastasis. Cancer Res 67(21):10582–10591CrossRefGoogle Scholar
  11. 11.
    Spillman MA, Manning NG, Dye WW, Sartorius CA, Post MD, Harrell JC, Jacobsen BM, Horwitz KB (2010) Tissue-specific pathways for estrogen regulation of ovarian cancer growth and metastasis. Cancer Res 70(21):8927–8936CrossRefGoogle Scholar
  12. 12.
    Sadikot RT, Blackwell TS (2005) Bioluminescence imaging. Proc Am Thorac Soc 2(6):537–540, 511–512CrossRefGoogle Scholar
  13. 13.
    Flanagan SP (1966) 'Nude', a new hairless gene with pleiotropic effects in the mouse. Genet Res 8(3):295–309CrossRefGoogle Scholar
  14. 14.
    Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, Kotb M, Gillies SD, King M, Mangada J, Greiner DL, Handgretinger R (2005) Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol 174(10):6477–6489CrossRefGoogle Scholar
  15. 15.
    Alzubi MA, Sohal SS, Sriram M, Turner TH, Zot P, Idowu M, Harrell JC (2019) Quantitative assessment of breast cancer liver metastasis expansion with patient-derived xenografts. Clin Exp Metastasis 36(3):257–269CrossRefGoogle Scholar
  16. 16.
    Alzubi MA, Turner TH, Olex AL, Sohal SS, Tobin NP, Recio SG, Bergh J, Hatschek T, Parker JS, Sartorius CA, Perou CM, Dozmorov MG, Harrell JC (2019) Separation of breast cancer and organ microenvironment transcriptomes in metastases. Breast Cancer Res 21(1):36CrossRefGoogle Scholar
  17. 17.
    Murray GF, Turner TH, Leslie KA, Alzubi MA, Guest D, Sohal SS, Teitell MA, Harrell JC, Reed J (2018) Live cell mass accumulation measurement non-invasively predicts carboplatin sensitivity in triple-negative breast cancer patient-derived xenografts. ACS Omega 3(12):17687–17692CrossRefGoogle Scholar
  18. 18.
    Turner TH, Alzubi MA, Sohal SS, Olex AL, Dozmorov MG, Harrell JC (2018) Characterizing the efficacy of cancer therapeutics in patient-derived xenograft models of metastatic breast cancer. Breast Cancer Res Treat 170(2):221–234CrossRefGoogle Scholar
  19. 19.
    Baklaushev VP, Kilpelainen A, Petkov S, Abakumov MA, Grinenko NF, Yusubalieva GM, Latanova AA, Gubskiy IL, Zabozlaev FG, Starodubova ES, Abakumova TO, Isaguliants MG, Chekhonin VP (2017) Luciferase expression allows bioluminescence imaging but imposes limitations on the orthotopic mouse (4T1) model of breast cancer. Sci Rep 7(1):7715CrossRefGoogle Scholar
  20. 20.
    Steinbauer M, Guba M, Cernaianu G, Kohl G, Cetto M, Kunz-Schughart LA, Geissler EK, Falk W, Jauch KW (2003) GFP-transfected tumor cells are useful in examining early metastasis in vivo, but immune reaction precludes long-term tumor development studies in immunocompetent mice. Clin Exp Metastasis 20(2):135–141CrossRefGoogle Scholar
  21. 21.
    Stripecke R, Carmen Villacres M, Skelton D, Satake N, Halene S, Kohn D (1999) Immune response to green fluorescent protein: implications for gene therapy. Gene Ther 6(7):1305–1312CrossRefGoogle Scholar
  22. 22.
    Andersson G, Denaro M, Johnson K, Morgan P, Sullivan A, Houser S, Patience C, White-Scharf ME, Down JD (2003) Engraftment of retroviral EGFP-transduced bone marrow in mice prevents rejection of EGFP-transgenic skin grafts. Mol Ther 8(3):385–391CrossRefGoogle Scholar
  23. 23.
    Day CP, Carter J, Weaver Ohler Z, Bonomi C, El Meskini R, Martin P, Graff Cherry C, Feigenbaum L, Tuting T, Van Dyke T, Hollingshead M, Merlino G (2014) "Glowing head" mice: a genetic tool enabling reliable preclinical image-based evaluation of cancers in immunocompetent allografts. PLoS ONE 9(11):e109956CrossRefGoogle Scholar
  24. 24.
    Dongre A, Rashidian M, Reinhardt F, Bagnato A, Keckesova Z, Ploegh HL, Weinberg RA (2017) Epithelial-to-mesenchymal transition contributes to immunosuppression in breast carcinomas. Cancer Res 77(15):3982–3989CrossRefGoogle Scholar
  25. 25.
    Gibby K, You WK, Kadoya K, Helgadottir H, Young LJ, Ellies LG, Chang Y, Cardiff RD, Stallcup WB (2012) Early vascular deficits are correlated with delayed mammary tumorigenesis in the MMTV-PyMT transgenic mouse following genetic ablation of the NG2 proteoglycan. Breast Cancer Res 14(2):R67CrossRefGoogle Scholar
  26. 26.
    Dunham LJ, Stewart HL (1953) A survey of transplantable and transmissible animal tumors. J Natl Cancer Inst 13(5):1299–1377PubMedGoogle Scholar
  27. 27.
    Carlson P, Dasgupta A, Grzelak CA, Kim J, Barrett A, Coleman IM, Shor RE, Goddard ET, Dai J, Schweitzer EM, Lim AR, Crist SB, Cheresh DA, Nelson PS, Hansen KC, Ghajar CM (2019) Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy. Nat Cell Biol 21(2):238–250CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2020

Authors and Affiliations

  1. 1.Integrative Life Sciences ProgramVirginia Commonwealth UniversityRichmondUSA
  2. 2.Department of PathologyVirginia Commonwealth UniversityRichmondUSA
  3. 3.Massey Cancer CenterVirginia Commonwealth UniversityRichmondUSA

Personalised recommendations